title: Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin.
abstract: Hematopoietic cell transplant (HCT) is a life-saving therapy for many malignant and non-malignant bone marrow diseases. Associated morbidities are often due to transplant-related toxicities and infections, exacerbated by regimen-induced immune suppression and systemic incursion of bacterial products. Patients undergoing myeloablative conditioning for HCT become endotoxemic and display blood/plasma changes consistent with lipopolysaccharide (LPS)-induced systemic innate immune activation. Herein, we addressed whether patients scheduled for HCT display differences in recognition/response to LPS ex vivo traceable to specific single nucleotide polymorphisms (SNPs). Two SNPs of LPS binding protein (LBP) were associated with changes in plasma LBP levels, with one LBP SNP also associating with differences in efficiency of extraction and transfer of endotoxin to myeloid differentiation factor-2 (MD-2), a step needed for activation of TLR4. None of the examined SNPs of CD14, bactericidal/permeability-increasing protein (BPI), TLR4 or MD-2 were associated with corresponding protein plasma levels or endotoxin delivery to MD-2, but CD14 and BPI SNPs significantly associated with differences in LPS-induced TNF-α release ex vivo and infection frequency, respectively. These findings suggest that specific LBP, CD14 and BPI SNPs might be contributory assessments in studies where clinical outcome may be affected by host response to endotoxin and bacterial infection.
authors.affiliation: Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Guinan
authors.affiliation: Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, MA, USA.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Palmer
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Christy J
authors.initials: CJ
authors.lastname: Mancuso
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Brennan
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Liat
authors.initials: L
authors.lastname: Stoler-Barak
authors.affiliation: Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Kalish
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Eugenie E
authors.initials: EE
authors.lastname: Suter
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Leighanne C
authors.initials: LC
authors.lastname: Gallington
authors.affiliation: University of Iowa and Veterans' Administration Medical Center, Coralville, Iowa City, IA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Huhtelin
authors.affiliation: Department of Pediatrics, University of Iowa, IA, Iowa City, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Mansilla
authors.affiliation: Institute for Microbiology, Charité-University Medical Center, Berlin, Germany.
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.affiliation: Department of Pediatrics, University of Iowa, IA, Iowa City, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: University of Iowa and Veterans' Administration Medical Center, Coralville, Iowa City, IA, USA.
authors.forename: Jerrold
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA ofer.levy@childrens.harvard.edu.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics; D001855:Bone Marrow Diseases / Q000235:genetics* / Q000628:therapy*; D002352:Carrier Proteins / Q000235:genetics; D018925:Chemokines / Q000378:metabolism; D015331:Cohort Studies; D004731:Endotoxins / Q000633:toxicity*; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D018925:Chemokines; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein
keywords: CD14; LPS-binding protein (LBP); TNF; bactericidal/permeability-increasing protein (BPI); bone marrow transplant; hematopoietic cell transplant (HCT); lipopolysaccharide (LPS)